Commentary
The recent pandemic of SARS-CoV-2 has emerged as a health emergency to develop effective therapeutic strategies for restricting deadly disease, COVID-19. SARS-CoV-2 infects cells by the endocytosis process via receptor-mediated binding and priming by cellular proteases [1,2]. However, the virus replicates in autophagosomes like structures in the cytosol by escaping endolysosomes pathway and develops acute respiratory syndrome by inducing cytokine storms [3-6]. Endolysosomes are acidic organelles that contain ~60 acid hydrolases capable of catalyzing the degradation of viral particles, enhancing endolysosome acidification might suppress SARS-CoV-2 infection [4,7-9]. The acidic nature of endolysosomes regulates endolysosomes’ functions and the autophagy degradation pathway [8,10,11]. Multiple endolysosomes-associated proteins such as v-ATPase (vacuolar-ATPase) [12,13], TRPML1 (mucolipin-1) and BK channels (Maxi-potassium) [14], two-pore channels [15], SLC38A9 (solute carrier family 38 member 9) [16-18], and mTOR (mammalian target of rapamycin) [19-21], regulate the acidic nature of lysosomes.
mTOR downstream signaling pathways regulate fundamental cellular processes such as metabolism, transcription, protein synthesis, apoptosis, cell cycle, endolysosomes, autophagy, and immune regulation and tolerance [22-26]. However, disturbed mTOR signaling is involved in various pathological conditions such as cardiovascular, cancer, inflammation, and metabolic disorders [23,26,27]. Besides, various viruses like influenza [28], HIV-1 [29,30], and coronaviruses, MERS-CoV [31] and SARS-CoV-2 [32-34], to complete viruses’ replication and life cycles, can hijack it. Recently, it has been identified that the SARS-CoV-2 virus exploits the mTOR-signaling pathway to progress the infection [33,35]; however, mTOR inhibitors suppress virus infection at a significant level with nanomolar concentrations [35]. The mTOR-signaling pathway has also been used to block several other viruses’ infection and replications by inducing autophagy and inhibiting viral protein synthesis [36-40]. Hence, mTOR could be an excellent therapeutic target to suppress the SARS-CoV-2 infection and COVID-19 using synthetic and natural compounds [41-43] (Figure 1). Thereby, various drugs are suggested and used to treat SARS-CoV-2 infection and COVID-19 pathogenesis like sapanisertib, metformin [44,45], rapamycin [46,47], and rapalog (everolimus) [39,48], which target the mTOR-signaling pathway. Recently, rapalog has been shown a protective role in small samples of COVID-19 aged patients [47-50]. Rapalog, an analog of rapamycin, is commonly used as an immunosuppressant [51]. However, it exerts immunostimulatory effects, for example, enhancing T-cell response in microbes’ infection and behaving as an immunoadjuvant in vaccination [52]. Hence, a placebo study should be conducted to explore and screen existed rapamycin like synthetic and natural compounds against SARS-CoV-2 infection and COVID-19 in vitro and in vivo conditions [43]. Table 1 contains the list of clinical trials of natural and synthetic mTOR inhibitors against COVID-19.
|
mTOR inhibitors |
Clinical trials’ References |
|
Sirolimus |
NCT04461340 |
|
Sirolimus |
NCT04341675 |
|
Sirolimus |
NCT04371640 |
|
RTB101 |
NCT04409327 |
|
Metformin |
|
|
Resveratrol [43] |
NCT04542993 |
|
Quercetin [43] |
NCT04377789 |
Figure 1. The mTOR sensor is exploited by SARS-CoV-2 for replication and survives in cells. However, mTOR inhibitors could suppress SARS-CoV-2 replication and COVID-19 by inducing autophagy, restricting the synthesis of viral proteins and inflammation.
Here briefly concludes that the mTOR sensor might be a potential therapeutic target to suppress SARS-CoV-2 infection and its pathogenesis, COVID-19. Hence, mTOR inhibitors, synthetic and mainly naturally available compounds, should be screened to determine their potency to suppress SARS-CoV-2 infection and COVID-19.
Conflict of Interest
No conflict of Interest reported.
Funding
This work was partly supported by NIH grant RO1 (MH119000).
References
2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020 Apr 16;181(2):271-80.
3. Wolff G, Limpens RW, Zevenhoven-Dobbe JC, Laugks U, Zheng S, de Jong AW, et al. A molecular pore spans the double membrane of the coronavirus replication organelle. Science. 2020 Sep 11;369(6509):1395-8.
4. Khan N, Chen X, Geiger JD. Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments. Frontiers in Pharmacology. 2020;11.
5. Snijder EJ, Van Der Meer Y, Zevenhoven-Dobbe J, Onderwater JJ, Van Der Meulen J, Koerten HK, et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. Journal of Virology. 2006 Jun 15;80(12):5927-40.
6. Geiger JD, Khan N, Murugan M, Boison D. Possible role of adenosine in COVID-19 pathogenesis and therapeutic opportunities. Frontiers in Pharmacology. 2020;11.
7. Yang N, Shen HM. Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19. International Journal of Biological Sciences. 2020;16(10):1724.
8. Bright NA, Davis LJ, Luzio JP. Endolysosomes are the principal intracellular sites of acid hydrolase activity. Current Biology. 2016 Sep 12;26(17):2233-45.
9. Khan N. Possible protective role of 17β-estradiol against COVID-19. Journal of Allergy and Infectious Diseases. 2020;1(2):38.
10. Khan N, Haughey NJ, Nath A, Geiger JD. Involvement of organelles and inter-organellar signaling in the pathogenesis of HIV-1 associated neurocognitive disorder and Alzheimer’s disease. Brain Research. 2019 Nov 1;1722:146389.
11. Truschel ST, Clayton DR, Beckel JM, Yabes JG, Yao Y, Wolf-Johnston A, et al. Age-related endolysosome dysfunction in the rat urothelium. PLoS One. 2018 Jun 8;13(6):e0198817.
12. Colacurcio DJ, Nixon RA. Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Research Reviews. 2016 Dec 1;32:75-88.
13. Collins MP, Forgac M. Regulation of V-ATPase assembly in nutrient sensing and function of V-ATPases in breast cancer metastasis. Frontiers in Physiology. 2018 Jul 13;9:902.
14. Khan N, Lakpa KL, Halcrow PW, Afghah Z, Miller NM, Geiger JD, et al. BK channels regulate extracellular Tat-mediated HIV-1 LTR transactivation. Scientific Reports. 2019 Aug 22;9(1):1-4.
15. Khan N, Halcrow PW, Lakpa KL, Afghah Z, Miller NM, Dowdy SF, et al. Two-pore channels regulate Tat endolysosome escape and Tat-mediated HIV-1 LTR transactivation. The FASEB Journal. 2020 Mar;34(3):4147-62.
16. Rebsamen M, Pochini L, Stasyk T, de Araújo ME, Galluccio M, Kandasamy RK, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015 Mar;519(7544):477-81.
17. Shen K, Sabatini DM. Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proceedings of the National Academy of Sciences. 2018 Sep 18;115(38):9545-50.
18. Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, et al. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015 Jan 9;347(6218):188-94.
19. Hu Y, Carraro-Lacroix LR, Wang A, Owen C, Bajenova E, Corey PN, Brumell JH, Voronov I. Lysosomal pH plays a key role in regulation of mTOR activity in osteoclasts. Journal of Cellular Biochemistry. 2016 Feb;117(2):413-25.
20. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science. 2011 Nov 4;334(6056):678-83.
21. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, et al. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell. 2013 Feb 14;152(4):778-90.
22. Das A, Reis F, Mishra PK. mTOR signaling in cardiometabolic disease, cancer, and aging 2018. Oxidative Medicine and Cellular Longevity. 2019; 2019: 9692528.
23. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012 Apr 13;149(2):274-93.
24. Nouwen LV, Everts B. Pathogens menTORing macrophages and dendritic cells: Manipulation of mTOR and cellular Metabolism to promote immune escape. Cells. 2020 Jan;9(1):161.
25. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annual Review of Immunology. 2012 Apr 23;30:39-68.
26. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017 Mar 9;168(6):960-76.
27. Weichhart T. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology. 2018;64(2):127-34.
28. Ranadheera C, Coombs KM, Kobasa D. Comprehending a killer: the Akt/mTOR signaling pathways are temporally high-jacked by the highly pathogenic 1918 influenza virus. EBioMedicine. 2018 Jun 1;32:142-63.
29. Akbay B, Shmakova A, Vassetzky Y, Dokudovskaya S. Modulation of mTORC1 Signaling Pathway by HIV-1. Cells. 2020 May;9(5):1090.
30. Martin AR, Pollack RA, Capoferri A, Ambinder RF, Durand CM, Siliciano RF. Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity. The Journal of Clinical Investigation. 2017 Feb 21;127(2):651-6.
31. Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, et al. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrobial Agents and Chemotherapy. 2015 Feb 1;59(2):1088-99.
32. Lehrer S. Inhaled biguanides and mTOR inhibition for influenza and coronavirus. World Academy of Sciences Journal. 2020 Mar 29;2(3):1-.
33. Appelberg S, Gupta S, Svensson AS, Ambikan AT, Mikaeloff F, Saccon E, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerging Microbes & Infections. 2020 Jan 1;9(1):1748-60.
34. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Marrero MC, et al. The global phosphorylation landscape of SARS-CoV-2 infection. Cell. 2020 Aug 6;182(3):685-712.
35. Garcia Jr G, Sharma A, Ramaiah A, Sen C, Kohn DB, Gomperts BN, et al. Antiviral drug screen of kinase inhibitors identifies cellular signaling pathways critical for SARS-CoV-2 replication. Available at SSRN 3682004. 2020 Jan 1.
36. Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infectious Diseases. 2017 Dec;17(1):1-0.
37. Maiese K. The mechanistic target of rapamycin (mTOR): novel considerations as an antiviral treatment. Current Neurovascular Research. 2020 Jun 1;17(3):332-7.
38. Zheng Y, Li R, Liu S. Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines. Journal of Medical Virology. 2020 Sep;92(9):1495-500.
39. Terrazzano G, Rubino V, Palatucci AT, Giovazzino A, Carriero F, Ruggiero G. An open question: is it rational to inhibit the mTor-dependent pathway as COVID-19 therapy?. Frontiers in Pharmacology. 2020 May 29;11:856.
40. Karam BS, Morris RS, Bramante CT, Puskarich M, Zolfaghari EJ, Lotfi-Emran S, et al. mTOR inhibition in COVID-19: A commentary and review of efficacy in RNA viruses. Journal of Medical Virology. 2021 Apr;93(4):1843-6.
41. Huang S. Inhibition of PI3K/Akt/mTOR signaling by natural products. Anti-Cancer Agents in Medicinal Chemistry. 2013 Sep;13(7):967.
42. Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, et al. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. Journal of Experimental Therapeutics & Oncology. 2009;8(1):25.
43. Khan N, Chen X, Geiger JD. Possible Therapeutic Use of Natural Compounds Against COVID-19. J Cell Signal 2021; 2(1): 63-79.
44. Scheen AJ. Metformin and COVID-19: From cellular mechanisms to reduced mortality. Diabetes & Metabolism. 2020 Nov 1;46(6):423-6.
45. Bramante C, Ingraham N, Murray T, Marmor S, Hoversten S, Gronski J, et al. Observational study of metformin and risk of mortality in patients hospitalized with Covid-19. Medrxiv. 2020 Jan 1.
46. Husain A, Byrareddy SN. Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19. Chemico-Biological Interactions. 2020 Oct 6:109282.
47. Omarjee L, Janin A, Perrot F, Laviolle B, Meilhac O, Mahe G. Targeting T-cell senescence and cytokine storm with rapamycin to prevent severe progression in COVID-19. Clinical Immunology (Orlando, Fla.). 2020 Jul;216:108464.
48. Zhavoronkov A. Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections. Aging (Albany NY). 2020 Apr 30;12(8):6492.
49. Bischof E, Siow RC, Zhavoronkov A, Kaeberlein M. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. The Lancet Healthy Longevity. 2021 Feb 1;2(2):e105-11.
50. Saha RP, Singh MK, Samanta S, Bhakta S, Mandal S, Bhattacharya M, et al. Repurposing drugs, ongoing vaccine and new therapeutic development initiatives against COVID-19. Frontiers in Pharmacology. 2020;11:1258.
51. Bak S, Tischer S, Dragon A, Ravens S, Pape L, Koenecke C, et al. Selective effects of mTOR inhibitor sirolimus on naïve and CMV-Specific T cells extending its applicable range beyond immunosuppression. Frontiers in Immunology. 2018 Dec 17;9:2953.
52. Ferrer IR, Araki K, Ford ML. Paradoxical aspects of rapamycin immunobiology in transplantation. American Journal of Transplantation. 2011 Apr;11(4):654-9.